Effects of central administation of probenecid on fevers produced by leukocytic pyrogen and PGE2 in the rabbit.

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Abstract
Single intracerebroventricular (i.c.v.) injections of probenecid (PBCD, 0.125-0.5 mg) enhanced and prolonged fever caused by i.v. administration of leukocytic pyrogen (LP) in rabbits resting in neutral (23.degree. C), cold (10.degree. C) and hot (30.degree. C) environments. Similar effects were produced by single i.c.v. injections of PBCD given before PGE2 [prostaglandin E2] (0.5 .mu.g) was injected i.c.v. in the three ambient temperatures. Fever produced by i.v. LP was also prolonged by infusion and by multiple injections of PBCD. PBCD given i.p. (100 mg/kg) enhanced and prolonged fever caused by i.v. injection of Salmonella typhosa endotoxin. Hyperthermia produced by i.c.v. PGE2 was not augmented by subsequent PBCD infusion. Pre-treatment with PBCD followed by PGE2 injection and PBCD infusion caused hyperthermia that was very high and prolonged, and, in some cases, lethal. Acetaminophen (2 mg, i.c.v.) and indomethacin (10 mg/kg, i.v.) lowered body temperature when given during fever induced by LP and prolonged by PBCD infusion. The concentration of PGE in (CSF) samples taken from the third or lateral ventricles rose of stabilized during PBCD infusions made during LP fever. Similar changes in PGE concentration also occurred during control infusions when body temperature was low. Termination of the actions of both central endogenous pyrogen and centrally administered PGE2, and the subsequent reductionof fevers produced by them, require a PBCD-sensitive facilitated transport system. The reduction of PBCD-prolonged LP fevers by antipyretics which block PGE synthesis suggests that prolongation by PBCD of LP fever is not due to blockade of PGE transport in a subsequent step in fever mediation per se, but is due to inhibition of transport of LP itself, or of other mediators associated with it.